Process for preparing oximes, hydrazones and semicarbazones of unreactive carbonyl compounds



,is much less reactive than acetone.

United States Patent 3,256,331 PROCESS FOR PREPARING OXIMES, HYDRA-ZONES AND SEMICARBAZONES 0F UNRE- ACTHVE CARBONYL COMPOUNDS William H.Jones, Metuchen, and Edward W. Tristram,

Cranford, N.J., assignors to Merck & Co., Inc., Rahway, N.J., acorporation of New Jersey No Drawing. Application July 28, 1959, Ser.No. 829,989, which is a division of application Ser. No. 646,520, Mar.18, 1957. Divided and this application Apr. 24, 1963, Ser. No. 275,227

4 Claims. (Cl. 260566) This application is a division of our copendingapplication Serial No. 829,989 filed July 28, 1959, and now abandoned,which is in turn a division of copending application Serial No. 646,520filed March 18, 1957, and now abandoned.

This invention relates to a novel process for the preparation ofunsaturated nitrogenous derivatives of carbonyl compounds and to thenovel products thus obtained.

The carbonyl group is characterized by unsaturation and ability to add agreat variety of reagents. This ability is modified, however, by thegroups attached to the carbonyl. Thus the methyl ketones containing thegrouping CH CO are more reactive than those which contain two largergroups. Branching of the groups, especially near the carbonyl, has aprofound effect on the activity of that group. For example,2,4-dimethyl-3-pentanone When the groups next to the carbonyl group arefurther substituted by methyl groups as in2,2,4,4-tetramethyl-3-pentanone, the carbonyl group becomes completelyunreactive toward such reagents as hydroxylamine, semicarbazide,hydrazine, etc. under any of the usual conditions for reaction with suchreagents. This invention is directed to the introduction of a nitrogenatom into just such unreactive compounds.

It is an object of this invention to provide a procedure for introducinga nitrogen atom in place of the oxygen atom of the carbonyl group wheresuch carbonyl group is generally unreactive.

The novel unsaturated nitrogenous derivatives of carbonyl compoundsproduced in accordance with this invention have been found to serve avariety of useful purposes. The oxirne derivatives are useful flotationagents, photographic sensitizers and rubber vulcanization agents. Thehydrazone derivatives are useful intermediates for making pyrazolonedyes and wetting agents. The semicarbazones possess insecticidalactivity. The amino derivatives obtained from the oximes have been foundto possess ganglionic blocking activity. The steroid derivatives may beconverted to compounds having cortisonelike activity.

Regarded in certain of its broader aspects, the process in accordancewith the present invention involves reacting a compound having anunreactive carbonyl group with a nitrogenous carbonyl addition reagentunder elevated pressure to form the unsaturated nitrogenous derivativeof said carbonyl compound. Although the examples set forth in thisinvention describe a batchwise operation, the process may be carried outin a continuous manner by suitable modifications of the apparatus. Ifdesired, the nitrogenous-containing product can then be reduced bychemical reducing agents or by catalytic hydrogenation to thecorresponding saturated nitrogenous compound which may be an amine,substituted hydrazine, etc., depending on the nature of the unsaturatednitrogenous derivative. The catalytic hydrogenation may likewise becarried out in either a batchwise or continuous manner.

In general, it may be said that the process in accordance with thepresent invention can be applied to any type of carbonyl compound, butit finds its novel and most useful application in effecting the reactionof unreactive carbonyl compounds. By the term unreactive carbonylcompound is meant compounds whose carbonyl groups are especiallyunreactive as a result of electronic or steric hindrance effects orcombinations of these effects.

The carbonyl groups which are especially unreactive may be determined bya color test described in Shriner, Fuson, Curtin The SystematicIdentification of Organic Compounds, Fourth Edition, page 119, 1956,John Wiley & Sons, Inc., New York. A brief description of this test isgiven below.

vThe reagent used in this test is prepared by adding 3 ml. of Bogen orGrammercy Universal Indicator to a solution of 5 grams of hydroxylaminehydrochloride in 1 m1. of ethanol. The color of the solution is adjustedto a bright orange shade (pH 3.7 to 3.9) by adding dilute (5%) ethanolicsodium hydroxide solution dropwise. The test involves adding to one ml.of this reagent a drop or few crystals of the carbonyl compound. Ifthere is no color change an unreactive carbonyl group is present. Theabove references describe a modification which is used for acidic orbasic compounds.

The compounds'which may be employed in the present process include thealiphatic saturated ketones where both carbon atoms are each attached.to at least two other carbon atoms or groups other than hydrogen as in2,2,4, 4-tetramethyl-3-pentanone; aliphatic unsaturated ketones whereboth tit-carbon atoms are each attached to at least two groups otherthan hydrogen except that when one of the iii-carbon atoms is part ofthe unsaturated grouping it must be attached to one other group otherthan hydrogen such as 2,4,4-trimethyl-l-penten-3-one; aliphaticdiketones in which all carbon atoms attached to the carbonyl groups aresubstituted by at least two groups other than hydrogen as in2,4,4,6-tetramethyl-3,S-heptanedione; cyclic ketones in which bothcarbon atoms attached to the carbonyl groups are each substituted by atleast one group other than hydrogen such as 2,5-dimethylcyclopentanone,and polycyclic ketones whose carbonyl groups are particularly unreactiveby virtue of the steric arrangement of the ring system and attachedgroups such as 22-ergosten-35-ol-1l-one; aromatic ketones in which atleast three of the ortho positions of the aromatic rings are substitutedby groups other than hydrogen such as2,6-dimethyl-2'-bromo-6'-nitrobenzophenone; mixed aromatic-aliphaticketones in which at least one of the ortho positions of the ring issubstituted by a group other than hydrogen and the u-carbon of thealiphatic portion holds at least two groups other than hydrogen such ascant-dimethyl-Z-nitropropiophenone; and 1,4-benzoquinones in which atleast three of the carbon atoms attached to carbonyl groups aresubstituted by groups other than hydrogen.

This invention also relates to unreactive aldehydes such as2,4-dinitrobenzaldehyde and 1,3-dinitro-2-naphthaldehyde.

By nitrogenous carbonyl addition reagent is meant compounds such ashydroxylamine, methoxylamine, aniline, benzylamine, ammonia, hydrazine,phenylhydrazine, semicarbazide and thiosemicarbazide, which react byaddition to the carbonyl group followed by elimination of water to formthe unsaturated nitrogenous carbonyl derivative.

In accordance with one method of carrying out the presentinvention,.sodium acetate trihydrate and hydroxylamine hydrochloride aredissolved separately in minimum amounts of water at room temperature.The solutions are mixed and diluted with ethanol and the sodium chloridewhich precipitates is removed. Thus, this procedure provides freehydroxylamine in a buffered solution. A ketone such as2,2,4,4-tetramethyl-3-pentanone is dissolved in the hydroxylaminesolution by dilution with ethanol. The reaction mixture is thencompressed hydraulically to at least 50,000 psi. The temperature of thereaction can range between room temperature and about 250 C. Thepressure is released and the white crystalline2,2,4,4-tetramethyl-3-pentanone oxime is filtered and washed with water.The 2,2,4,4-tetramethyl-3- pentanone oxime thus obtained can be used asa flotation agent, photographic sensitizer or rubber vulcanizationagent.

The 2,2,4,4-tetramethyl-3-pentanone oxime can then be hydrogenated inthe presence of a hydrogenation catalyst such as platinum oxide orpalladium to form 3-amino- 2,2,4,4-tetramethylpentane.

The following examples are intended to be illustrative only and may bevaried or modified without departing from the spirit and scope of thisinvention.

EXAMPLE 1 Preparation of 2,2,4,4-tetramethyl-S-pentanone oxime 5.4 gramsof sodium acetate trihydrate and 2.2 grams of hydroxylaminehydrochloride were dissolved separately in minimum amounts of water atroom temperature. The two solutions were then mixed and diluted to about40 ml. with absolute ethanol. The precipitate of sodium chloride wasremoved by filtration. Then 3.0 grams of 2,2,4,4-tetramethyl-3-pentanonewas dissolved in the above filtrate and the total volume of solution wasbrought to 50 ml. with absolute ethanol. This solution was transferredto a compressible stainless steel sample holder which was placed in ahigh pressure reaction vessel. The reaction mixture was then compressedhydraulically to a pressure of 125,000 psi. at room temperature. Thetemperature was raised to 75 C. at which point the pressure hadincreased to 136,000 p.s.i. These reaction conditions were maintainedfor a period of hours. The reactor was cooled to room temperature andthe pressure was then released. The sample holder was opened and thewhite crystalline 2,2,4,4-tetramethyl-3-pentanone oxime was filtered andwashed thoroughly with water. Removal of the ethanol from the filtrateby concentration in vacuo gave an additional small crop of crystallineproduct. The total weight of product was 2.3 g., M.P. 156.5158.5 C.

Reduction of 2,2,4,4-tetramethyl-3-pentanone oxime to3-amin0-2,2,4,4-tetramethylpentane CH NOH CE;

0.5 gram of 2,2,4,4-tetramethyl-3-pentanone oxime prepared as describedabove was dissolved in 15 ml. of glacial acetic acid and reduced in thepresence of 0.25 gram of platinum oxide at room temperature andaninitial hydrogen pressure of 42 psi. The reduction was allowed toproceed for about 15 hours during which time the theoretical amount ofhydrogen was absorbed. Then the catalyst was removed by filtration. T othe filtrate was added 0.5 m1. of concentrated hydrochloric acid, andthe mixture was concentrated to dryness in vacuo. The white crystallineresidue of 3-amino-2,2,4,4-tetramethylpentane hydrochloride wasrecrystallized from an ethanol-ether produced in accordance with theabove procedure possesses a relatively high order of ganglionic blockingactivity.

EXAMPLE 2 Preparation of 2,2,3,3,5,5,6-heptamethyl-4-heptan0neuemicarbazone CH (111 (H) CH CH 4.1 grams of sodium acetate trihydrateand 2.2 grams of semicarbazide hydrochloride were dissolved separatelyin minimum amounts of water at room temperature. The two solutions werethen mixed and diluted to about 40 ml. with absolute ethanol. Theprecipitate of sodium chloride was removed by filtration. Then 2.1 gramsof 2,2,3,3,5,5,6-heptamethyl-4-heptanone was dissolved in the abovefiltrate and the total volume was brought to 50 ml. with absoluteethanol. The reaction mixture was then placed in a sample holder andcompressed for 24 hours at 140,000 p.s.i. pressure at 100 C. Thereaction mixture was removed from the pressure vessel and concentratedin vacuo to remove most of the ethanol. The residue was diluted withwater and the desired white crystalline2,2,3,3,5,5,6-heptamethyl-4-heptanone semicarbazone was collected on afilter.

EXAMPLE 3 Preparation of 3,5-dichZora-2,6-dimethyl-1,4-benzoquinonedioxz'me o NOH II 11.0 OH! H30 0H3 i alf-oH :2 11 0 01 o1 H 01 or I I oN-OH To an aqueous ethanol solution of 2.8 grams of hydroxylaminehydrochloride and 6.8 grams of sodium acetate trihydrate was added 2.1grams of 3,5-dichloro- 2,6-dimethyl-1,4-benzoquinone. The reactionmixture was compressed hydraulically to 140,000 p.s.i. pressure at atemperature of C. These conditions were maintained for 12 hours. Thenthe ethanol was removed by concentration in vacuo and the crystalline5.,5-dichloro- 2,6-dimethyl-1,4,benzoquinone dioxime was. rQmQYQd. byfiltration.

- EXAMPLE 4 Preparation of2,2,6,6-tetramethylcyclonexanonephenylhydrazone CH CH3- ii FREQ NHz CHCH3 HIT-Q (EH3 In] 3 l CH CH3 4.1 grams of sodium acetate trihydrate and2.9 grams of phenylhydrazine hydrochloride were dissolved separately inminimum amounts of water at room temperature. The two solutions werethen mixed and diluted to about 40 ml. with absolute ethanol. Theprecipitate of sodium chloride was removed by filtration. Then 2.4 gramsof 2,2',6,6-tetramethylbenzophenone was dissolved in the above filtrateand the total volume of solution was brought to 50 ml. by the additionof absolute ethanol. The reaction mixture was then compressedhydraulically to a pressure of 125,000 p.s.i. at a temperature of 50 C.These conditions were maintained for 12 hours. Then the ethanol wasremoved by concentration in vacuo and the crystalline2,2,,6,6-tetramethylbenzophenone phenylhydrazone was removed byfiltration.

EXAMPLE 5 Preparation of 2,2,6,6-tetramethylcyclohexanone-4-nitrophenylhydrazone 13130 H CH To a mixture of 30 ml. of ethanol and0.5 ml. of glacial acetic acid was added 1.3 grams of2,2,6,6-tetramethylcyclohexanone and 2.3 grams of4-nitrophenylhydrazine. The mixture was diluted to a volume of about 50ml. and transferred to a compressible sample holder. The sample holderwas placed in the high pressure vessel and compressed hydraulically to apressure of 150,000 p.s.i. at a temperature of 50 C. for a period of 8hours. The reaction mixture was then concentrated to a small volume invacuo and cooled in ice. The crystalline 4- nitrophenylhydrazone of2,2,6,6 tetramethylcyclohexanone was collected on a filter andrecrystallized from a water-ethanol mixture.

Reduction of 2,2,6,6-tetramethylcyclohexan0ne-4-nitr0-2,2,6,6-tetramethylcyclohexanone was dissolved in 50 ml. of ethanol. Themixture was hydrogenated at room temperature over 0.5 gram of a 5%palladium on carbon catalyst. The initial hydrogen pressure was 40p.s.i. The theoretical amounts of hydrogen was absorbed in 45 minutes.The catalyst was removed by filtration and the filtrate was cooled inice and saturated with dry hydrogen chloride. The crystallinehydrochloride of 1 (4 am-inophenyl) 2 (2,2,6,6 tetramethylcyclohexyl)hydrazine was collected on a filter and washed with ether.

EXAMPLE- 6 Preparation of 3,20-bisethylenedi0xy-11-0ximin0- 5-pregnene 17a,21 -d1'0l CHiOH O V (L/ 1 To a solution of 3.0 grams of hydroxylaminehydrochloride and 6.0 grams of sodium acetate in 15 ml. of Water wereadded 15 ml. of ethanol and 25 ml. of pyridine. The precipitated saltwas removed by filtration. 3.0 grams of3,20-bisethylenedioxy-5-pregnene-1711,21- diol-ll-one was dissolved inthe filtrate and heated at 75 C. under 130,000 p.s.i. pressure for 16hours. cooling to room temperature, the reaction mixture was dilutedwith water and made alkaline with dilute sodium hydroxide. Thefiocculent precipitate was aged in the refrigerator for two hours,filtered, and washed with water. The crude product was recrystallizedfrom methanol to give 1.5 grams of pure3,20-bisethylenedioxyl1-oximino-5-pregnene-l7a,2l-diol, melting point259- 267 C., with decomposition. The infrared absorption spectrum showedno absorption in the carbonyl regions.

After CHQOH CHZOH I/ C CHrOH L/ D2. 6J2 tZ 6.0 grams of sodium was addedover a period of 2 hours to a refluxing solution of 1 gram of,ll-oximino- 3,20-bisethylenedioxy-5-pregnene-17a,21-diol in 70 ml. ofl-butanol. The reaction mixture after cooling was diluted with water andextracted with ether-butanol.

EXAMPLE 7 Preparation of 11-0ximin0-22-erg0sten-3fi-0l in minimumamounts of water.

The etherthe filtrate.

A mixture of 0.5 gram of 22-ergosten-3fl-ol-1l-one, 1.0

gram of hydroxylamine hydrochloride, and 2.0 grams of sodium acetatewere dissolved in a mixed solvent consisting of 10 ml. water, 20 ml.ethanol, and 10 ml. pyridine. The solution at high pressure (135,000p.s.i.) was heated at 75 C. for 18 hour-s. After cooling, the reactionmixture was diluted with ml. of water and filtered to give crude11-oximino-22-ergosten-3fi-ol having a melting point of -190 C.Recrystallization from methanol gave 0.35 g. of product, M.P. 193195 C.

EXAMPLE 8 Preparation of 2,4-dinitr0benzaldehyde oxime 5.4 grams ofsodium acetate trihydrate and 2.2 grams of hydroxylamine hydrochloridewere dissolved separately The two solutions were then mixed and dilutedto about 40 ml. with ethanol. The sodium chloride which precipitated wasfiltered, and 2.0 grams of 2,4-dinitrobenzaldehyde was dissolved in Thetotal volume of solution was brought to 50 ml. by the addition ofethanol. This reaction mixture was then compressed hydraulically to150,000 p.s.i. and heated at 50 C. for 12 hours. The reaction mixturewas then diluted with water and concentrated in vacuo to remove most ofthe ethanol. The oxime of 2,4-dinitrobenzaldehyde which precipitatedwascollected on a filter and washed with water.

Various changes andmodifications may be made in carrying out the presentinvention without departing from the spirit and scope thereof. Insofaras these changes and modifications are within the purview of the annexedclaims they are to be considered as part of this invention.

What is claimed is:

1. The process comprising reacting a compound se lected from the groupconsisting of aldehydes and ketones containing an unreactive carbonylgroup, which compound demonstrates an absence of color change when asmall portion of said compound is treated with 1 ml. of a test solutionof 3 mls. of a Bogen Universal Indicator in a solution of 5 gms. ofhydroxylamine hydrochloride in 1 ml. of 95 ethanol, which test solutionhas prior to the treatment of said compound had its pH adjusted tobetween' 3.73.9 (bright orange shade) by adding 5% ethanolic sodiumhydroxide solution thereto, with an amine compound selected from thegroup consisting of hydroxylamine, semicarbazide, phenylhydrazine, andnitrophenylhydrazine at a pressure in the range of 50,000 p.s.i. to150,000 p.s.i. and at a temperature within the range of room temperatureto about 250 C. to obtain the corresponding reaction product selectedfrom the group.

consisting of oximes, semicarbazones, and hydrazones, depending on theamine compound employed in the reaction.

2. The process according to claim 1 wherein the carbonyl compound isselected from the group consisting of 2,2,4,4 tetramethyl 3 pentanone,2,2,3,3,5,5,6 heptamethyl-4-heptanone,3,5-dichloro-2,6-dimethyl-1,4-benzoquinone, 2,2',6,6-tetramethylbenzophenone and 2,2,6,6- tetramethylcyclohexanone.

3. The process according to claim 1 wherein the carbonyl compound is2,2,4,4-tetramethyl-3-pentanone and the amine compound is hydroxylamine.

9 '10 4. The process according to claim 3 wherein the re- OTHERREFERENCES action is carried out at a pressure between 125,000 p.s.i.Bruzau Ann de Chim 11th Series Vol 1 pages and 136,000 p.s.i. 2 193i H79 I: Reierences Cited by the Examiner 5 2111512328; 211., Organicchemlstry, 2nd 141., PP- 213 FOREIGN PATENTS G ea Brit in- B. PrimaryExaminer-

1. THE PROCESS COMPRISING REACTING A COMPOUND SELECTED FROMTHE GROUPCONSISTING OF ALDEHYDES AND KETONES CONTAINING AN UNREACTIVE CARBONYLGROUP, WHICH COMPOUND DEMONSTRATES AN ABSENCE OF COLOR CHANGE WHEN ASMALL PORITON OF SAID COMPOUND IS TREATED WITH 1 ML. OF A TEST SOLUTIONOF 3 MLS. OF A BOGEN UNIVERSAL INDICATOR IN A SOLUTION OF 5 GMS. OFHYDROXYLAMINE HYDROCHLORIDE IN 1 ML. OF 95% ETHANOL, WHICH TEST SOLUTIONHAS PRIOR TO THE TREATMENT OF SAID COMPOUND HAD ITS PH ADJUSTED TOBETWEEN 3.7-3.9 (BRIGHT ORANGE SHADE) BY ADDING 5% ETHANOLIC SODIUMHYDROXIDE SOLUTION THERETO, WITH AN AMINE COMPOUND SELECTED FROM THEGROUP CONSISTING OF HYDROXYLAMINE, SEMICARBAZIDE, PHENYLHYDRAZINE, ANDNITROPHENYLHYDRAZINE AT A PRESSURE INTHE RANGE OF 50,000 P.S.I. TO150,000 P.S.I. AND AT A TEMPERATURE WITHIN THE RANGE OF ROOM TEMPERATURETO ABOUT 250*C. TO OBTAIN THE CORRESPONDING REACTION PRODUCT SELECTEDFROM THE GROUP CONSISTING OF OXIMES, SEICARBAZONES, AND HYDRAZONES,DEPENDING ON THE AMINE COMPOUND EMPLOYED IN THE REACTION.